Nabal, M., Librada, S., Redondo, M. J., Pigni, A., Brunelli, C., & Caraceni, A. (2012). The role of paracetamol and nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the control of pain in advanced cancer. A systematic review of the literature. Palliative Medicine, 26, 305–312.

To perform a systematic review of evidence of the efficacy and toxicity of nonsteroidal antiinflammatory drugs (NSAIDs) or paracetamol in addition to World Health Organization (WHO) step III opioid treatment for moderate to severe cancer pain in comparison to opioids alone

The type of study is systematic review.

Databases searched were MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials.
Search keywords were acetaminophen, paracetamol, neoplasm, pain, and NSAID.
Studies were included in the review if they were

• Written in English
• Had a publication date of 2002–2010
• Conducted with adult human participants experiencing chronic cancer pain
• A randomized controlled trial or a meta-analysis reporting on efficacy and/or side effects of NSAIDs or paracetamol in addition to opioids in comparison to opioids alone.

No specific exclusion criteria was identified.

A total of 803 references were retrieved. 

After further review by the authors, 12 studies were included in the literature review.

Each study was evaluated in terms of content and quality using the Cochrane Handbook for Systematic Reviews of Interventions as the tool for appraisal.

• A final number of 12 studies were included in the review.
• The total number of patient cases included in the review was 396.
• The article does not describe patient demographics or characteristics, including cancer diagnoses.

• Patients were undergoing multiple phases of care.
• The study has clinical applicability for palliative care.

Adjuvant use of NSAIDs has been demonstrated to provide an additive effect in either improving pain management or reducing opioid use. Paracetamol use did not demonstrate any significant improvement over opioid use alone.

The articles reviewed provide weak support of the addition of NSAIDs to WHO step III opioids to improve analgesia and/or reduce opioid dose amount. The addition of paracetamol in combination with step III opioids cannot be supported by the current research review.

Several limitations were identified during the process of systematic review, including small sample, large losses to follow-up, no intention-to-treat analysis completed, short follow-up (one to five days), and evidence of sponsorship by industries (bias).

This review adds to the body of evidence that routine use of acetaminophen to opioids for chronic pain management is not effective for pain reduction or reduction in opioid dosage needed for pain control. Acetaminophen does have potential negative effects with long-term or high-dose use, so this approach should not be implemented as a routine. A growing body of research is challenging the WHO ladder approach to pain management.